Ingrid Perez-Alvarez1, Somaye Yekezare1, X Frank Zhao2, Xiangdong Xu21 Department of Pathology, University of California at San Diego, San Diego, California, USA2 Department of Pathology, University of California at San Diego, San Diego, California; Department of VA San Diego Healthcare System, San Diego, California, USA

The present case is that of a 47-year-old Caucasian man who presented with fevers, decreased appetite, weakness, and abdominal pain for 1 month and 10 pound weight loss. There was no significant history of diarrhea. Further review of the charts identified a prior history of multi-joint disease for 3 years. Laboratory tests revealed iron deficiency anemia. Other abnormal laboratory findings included hypoalbuminemia (2.3 g/dL), elevated C-reactive protein (4.63 mg/dL), and elevated erythrocyte sedimentation rate (47 mm/h). Computed tomography of the abdomen showed mesenteric and retroperitoneal lymphadenopathy. Multiple laboratory tests for infectious etiologies, including HIV, Epstein-Barr virus, cytomegalovirus, hepatitis viruses, and tuberculosis, were all negative. An upper gastrointestinal endoscopy revealed prominent villi in the first and second parts of the duodenum. Biopsies from the duodenum and an enlarged axillary lymph node were submitted for histologic examination.

Sections of the lymph node revealed preserved nodal architecture with sinusoidal expansion, containing many histiocytes [Figure 2]a and b. PAS stain highlighted the same microorganisms within the histiocytes as those in the duodenal biopsy [Figure 2]c and d.

The differential diagnoses include Whipple disease (WD) and other infectious diseases. A portion of the lymph node specimen was sent for T.whipplei ribosomal RNA test by polymerase chain reaction (PCR), which confirmed the diagnosis of WD.

Whipple disease is a rare, potentially lethal, infectious disease involving multiple organs. The culprit is a Gram-positive bacillus, T. Whipplei. Since the first case reported by Dr. George Hoyt Whipple in 1907, there are approximately 1000 cases reported in the literature. [1] Majority of the patients are middle-aged Caucasian men with a history of exposure to soil and animals. Typically, WD starts with the prodromal stage of arthralgia and arthritis (73-85% of total cases). [1],[2] Often years later, the disease progresses to the steady stage and shows some typical symptoms include diarrhea (75-81% cases), abdominal pain (60% cases), weight loss (90-93% cases), and lymphadenopathy (45-52% cases). [1],[2] It is important to be aware that WD may have atypical presentations. Our patient had an atypical non-diarrheic presentation, and the correct diagnosis was 3 years later than the onset of arthropathy.

Even with the major scientific discoveries of T.whipplei in the past several decades, including cultivation methods, the genome, and new diagnostic methods, [1] timely diagnosis of WD is still a challenge due to its rarity and nonspecific clinical presentations. The initial workup of WD includes identification of PAS-positive organisms in tissue biopsies. It is important to be aware that PAS positivity is not specific for T.whipplei, and could also be seen in, for example, mycobacterial infection. Acid-fast stain is negative in WD and is useful to exclude mycobacteria. Lymph nodes, especially of the mesenteric region, are involved in approximately half of WD cases. There are two common histologic patterns of involved lymph nodes: "lipodystrophy" with ill-defined noncaseating lipogranulomas and "sinusoid histiocytosis." The lymph node of our case demonstrated the second pattern.

The best confirmatory test of WD is PCR amplifying the 16S ribosomal RNA of the organism, which can be done on either fresh tissue or formalin fixed paraffin embedded tissue. Alternative confirmatory tests of WD include immunohistochemistry, [3] electron microscopy, [4] and culture. [3] Immunohistochemistry has great sensitivity and specificity and can detect the organisms in tissues, body fluids, and infected monocytes. Electron microscopy reveals the trilaminar wall as a distinctive feature of T.whipplei. However, electron microscopy is used less frequently and has gradually lost its popularity to aforementioned new methods. Culture of T.whipplei can be performed only in a specialized laboratory and has very limited accessibility.

WD is universally lethal before the advent of antibiotics. The current recommended therapy initiate with streptomycin induction, plus either ceftriaxone or penicillin G for 2 weeks. Maintenance therapy use antibiotics crossing the blood-brain barrier (such as trimethoprim-sulfamethoxazole) for 1-2 years. [5] Our patient was started on Ceftriaxone 2 g daily and had prompt responses of increased appetite and weight gain within 2 weeks. Long-term follow-up is needed to ensure bacterial eradication.